Multiple myeloma (MM) is a hematological malignancy caused by malignant proliferation of plasma cells in bone marrow. Over the last decade, the survival outcome of patients with multiple myeloma (MM) ...has been substantially improved with the emergence of novel therapeutic agents. However, MM remains an incurable neoplastic plasma cell disorder. In addition, almost all MM patients inevitably relapse due to drug resistance. Chimeric antigen receptor (CAR)-modified NK cells represent a promising immunotherapeutic modality for cancer treatment. In this study, NK92 cells were engineered to express the third generation of BCMA CAR. In vitro, BCMA CAR-engineered NK92 cells displayed higher cytotoxicity and produced more cytokines such as IFN-γ and granzyme B than NK92 cells when they were co-cultured with MM cell lines. Furthermore, BCMA CAR-engineered NK92 cells released significantly higher amounts of cytokines and showed higher cytotoxicity when they were exposed to primary cells isolated from MM patients. The cytotoxicity of BCMA CAR NK92 cells was enhanced after MM cells were treated with bortezomib. Additionally, BCMA CAR NK92 cells exhibited potent antitumor activities in subcutaneous tumor models of MM. These results demonstrate that regional administration of BCMA CAR NK92 cells is a potentially promising strategy for treating MM.
Aplastic anemia (AA) is a lethal hematological disorder; however, its pathogenesis is not fully understood. Although immunosuppressive therapy (IST) is a major treatment option for AA, one‐third of ...patients do not respond to IST and its resistance mechanism remains elusive. To understand AA pathogenesis and IST resistance, we performed single‐cell RNA sequencing (scRNA‐seq) of bone marrow (BM) from healthy controls and patients with AA at diagnosis. We found that CD34+ early‐stage erythroid precursor cells and PROM1+ hematopoietic stem cells were significantly depleted in AA, which suggests that the depletion of CD34+ early‐stage erythroid precursor cells and PROM1+ hematopoietic stem cells might be one of the major mechanisms for AA pathogenesis related with BM‐cell hypoplasia. More importantly, we observed the significant enrichment of CD8+ T cells and T cell–activating intercellular interactions in IST responders, indicating the association between the expansion and activation of T cells and the positive response of IST in AA. Taken together, our findings represent a valuable resource offering novel insights into the cellular heterogeneity in the BM of AA and reveal potential biomarkers for IST, building the foundation for future precision therapies in AA.
In eukaryotes, entry into mitosis is induced by cyclin B‐bound Cdk1, which is held in check by the protein kinase, Wee1. In budding yeast, Swe1 (Wee1 ortholog) is targeted to the bud neck through ...Hsl1 (Nim1‐related kinase) and its adaptor Hsl7, and is hyperphosphorylated prior to ubiquitin‐mediated degradation. Here, we show that Hsl1 and Hsl7 are required for proper localization of Cdc5 (Polo‐like kinase homolog) to the bud neck and Cdc5‐dependent Swe1 phosphorylation. Mitotic cyclin (Clb2)‐bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5‐dependent Swe1 hyperphosphorylation and degradation. Clb2‐Cdc28 also facilitated Cdc5 localization to the bud neck through the enhanced interaction between the Clb2‐Cdc28‐phosphorylated Swe1 and the polo‐box domain of Cdc5. We propose that the concerted action of Cdc28/Cdk1 and Cdc5/Polo on their common substrates is an evolutionarily conserved mechanism that is crucial for effectively triggering mitotic entry and other critical mitotic events.
In a previous study, we reported that ginseng extract has anxiolytic-like effects in the elevated plus-maze model and that the ginseng saponin fraction plays an important role. This experiment was ...performed to investigate the anxiolytic-like effects of ginsenosides Rb1, Rg1, Rg3-R, and Rg3-S, and the Rg5 and Rk mixture isolated from the ginseng saponin fraction in the elevated plus-maze. Furthermore, the anxiolytic-effects of Rb1, Rg1, Rg3-R, Rg3-S, and the Rg5 and Rk mixture were compared with those of a well-known active anxiolytic drug (diazepam). The oral administration of ginsenoside Rb1 significantly increased the number of open arm entries and the time spent on the open arm compared with those in the vehicle-treated group. Ginsenoside Rg1 and the Rg5 and Rk mixture also significantly increased the number of open arm entries and the time spent on the open arm. However, ginsenosides Rg3-R and Rg3-S did not increase the number of open arm entries or the time spent on the open arm. On the other hand, ginsenoside Rb1 and the Rg5 and Rk mixture decreased locomotor activity in a manner similar to diazepam. These data indicate that ginsenosides Rb1, Rg1, and the Rg5 and Rk mixture have anxiolytic-like effects, but ginsenosides Rg3-R and Rg3-S do not in this model. We provide evidence that some ginsenosides may be useful for the treatment of anxiety.
APCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected ...with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.
A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure–activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was ...oriented towards modification of the potential metabolic soft spots (e.g., phenol and olefin) or by altering the polar surface area via incorporating heterocycles such as isoxazole and triazole. Most of all exhibited the inhibitory effects on COX-2 and PGF1 production but not macrophage NO production. Especially, aryl carbamates 10 and 11 exhibited more potent inhibitory activity against COX-2 and PGF1 production.
This study attempted to clarify whether cocaine withdrawal altered sleep architecture and the role of adenosine receptors in this process. Cocaine (20 mg/kg) was administered subcutaneously once per ...day for 7 days to rat implanted with sleep/wake recording electrode. Polygraphic signs of undisturbed sleep/wake activities were recorded for 24 h before cocaine administration (basal recording as control); withdrawal-day 1 (after 1 day of repeated cocaine administration), withdrawal-day 8 (after 8 days of repeated cocaine administration), and withdrawal-day 14 (after 14 days of repeated cocaine administration), respectively. On cocaine withdrawal-day 1, wakefulness was significantly increased, total sleep was decreased, non-rapid eye movement sleep was markedly reduced, and rapid eye movement sleep was enhanced. Sleep/wake cycles were also increased on cocaine withdrawal day 1. However, non-rapid eye movement sleep was increased on withdrawal-day 8 and 14, whereas rapid eye movement sleep was decreased and no significant changes were observed in the total sleep and sleep/wake cycles during these periods. Adenosine A
2A
receptors expression was increased on withdrawal-day 8 and 14, whereas A
1
receptors levels were reduced after 14 days of withdrawal and the A
2B
receptors remained unchanged. Our findings suggest that alterations of sleep and sleep architecture during cocaine subacute and subchronic withdrawals after repeated cocaine administration may be partially involved in A
2A
receptors over-expression in the rat hypothalamus.
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